1. Field of the Invention
This invention relates to new anthracycline glycoside antitumor antibiotics, to processes for their preparation and to pharmaceutical compositions containing them. More, particularly, it relates to new antitumor antibiotics designated MA 144-M.sub.1 and MA 144-M.sub.2, to processes for the preparation thereof by the fermentation of MA 144-producing strains belonging to streptomyces and by the chemical or enzymatic conversion of aclacinomycin A or cinerubin A, to methods for their recovery and purification, and to their application as chemotherapeutic agents for the inhibition of malignant tumors and for the treatment of infectious diseases caused by gram-positive bacteria.
2. Description of the Prior Art
A number of anthracycline glycosides have been found in the cultured broth of streptomyces. Among them, daunomycin and adriamycin have already been applied clinically for human cancers. In the continuation of the study of antitumor antibiotics, especially anthracycline glycosides produced by Streptomyces galilaeus MA 144-M.sub.1, the present inventors discovered new compounds and after purification and characterization based on their physico-chemical properties, they confirmed that the antibiotics now names MA 144-M.sub.1 and MA 144-M.sub.2 are new compounds which have potent antitumor activity and low toxicity in animals, and they established processes and methods for their preparation and purification.
Aclacinomycin A is disclosed in U.S. Pat. No. 3,988,315 and by Oki et al. in J. Antibiotics 28: 830 (1975).
Cinerubin A and cinerubin B are disclosed in U.K. Pat. No. 846,130, U.S. Pat. No. 3,864,480, Keller-Schierlein et al., "Antimicrobial Agents and Chemotherapy", page 68 (1970), Chemical Abstracts 54: 1466 i (1960) and J. Antibiotics 28: 830 (1975).
Other anthracycline antibiotics having aklavinone or .epsilon.-pyrromycinone aglycone moieties are disclosed in the literature as follows:
(a) Pyrromycin: Chem. Ber. 92: 1904-1909 (1959). PA1 (b) Rutilantin: Biochem. J. 81: 101-104 (1961). PA1 (c) Galirubin A and B: Naturwiss. 52: 539-540 (1965). Chemical Abstracts 64: 3896 g (1966). Chemical Abstracts 67: 90573 z (1967). PA1 (d) Aklavin: J. Bacteriol. 72: 90 (1956). PA1 (e) Requinomycin: J. Antibiotics 25: 393 (1972). PA1 yellow powder with m.p. 149.degree.-150.degree. C. PA1 Empirical formula: C.sub.42 H.sub.55 O.sub.15 N PA1 Ultraviolet and visible absorption maxima at: 229(775), 258(335), 290(128), 432(155) nm in methanol, 229(815), 259(345), 290(130), 432(160) nm in 0.01N HCl-methanol and 237(575), 250s(405), 290(125), 323s(80), 526(135) nm in 0.01N NaOH-methanol. PA1 red needle crystals with m.p. 151.degree.-152.degree. C. PA1 Empirical formula: C.sub.42 H.sub.55 O.sub.16 N PA1 Ultraviolet and visible absorption maxima at: 235(600), 259(310), 269(170), 291(105), 492(165) nm in methanol, 235(615), 259(325), 269(185), 291(115), 492(170) nm in 0.01N HCl-methanol, and 237(505), 269(145), 292(95), 330(55), 554 (175), 597(145) nm in 0.01N NaOH-methanol.
For further illustrative and summary disclosures of anthracycline antibiotics, see Index of Antibiotics from Actinomycetes, Hamao Umezawa, Editor-in-chief, University Park Press, State College, Pennsylvania, U.S.A. (1967) as follows:
______________________________________ Antibiotic Page Number ______________________________________ Aklavin 111 Cinerubin A 220 Cinerubin B 221 Pyrromycin 542 ______________________________________
The textbook Antibiotics, Volume 1, Mechanisms of Action, edited by David Gottlieb and Paul D. Shaw, Springer-Verlag New York, Inc., N.Y., N.Y. (1967) at pages 190-210 contains a review by A. DiMarco entitled Daumycin and Related Antibiotics.
Information Bulletin, No. 10, International Center of Information of Antibiotics, in collaboration with WHO, December, 1972, Belgium, reviews anthracyclines and their derivatives.
This specification refers to disclosures on amicetin: see J. Am. Chem. Soc. 86: 3592 (1964).
For a description of Streptomyces galilaeus, see Arch. fur Mikrobiol. 31: 356 (1958) and International Journal of Systematic Bacteriology 22: 298 (1972).